Peripheral neuropathy is the most common complication of diabetes and will afflict over half of the 25 million Americans who currently suffe from the disease. There is no FDA-approved therapy to reverse the distal degenerative neuropathy that is already present in many newly diagnosed diabetic patients and which gets progressively worse over time. Recent clinical and experimental studies have demonstrated that the retraction of peripheral terminals of small sensory axons from the epidermis of the skin is an early feature of diabetic neuropathy. This offers an opportunity to halt or reverse the dying-back of peripheral terminals before neuronal death occurs. Our preclinical studies have demonstrated that structurally diverse muscarinic receptor antagonists such as pirenzepine, VU0255035, MT-7 and oxybutynin promote axonal growth from sensory neurons of adult rats in vitro and that this class of drugs also prevents loss of intra-epidermal nerve fibers (IENF) and other features of neuropathy in rodent models of type 1 and type 2 diabetes. It therefore appears that adult peripheral neurons are under constant endogenous cholinergic constraint of axonal growth. The practical application of this knowledge is that muscarinic receptor antagonists may be viable and novel therapeutics for reversing early diabetic neuropathy. The FDA has recently approved use of the muscarinic receptor antagonist oxybutynin (Gelnique 3%TM) as a daily topical therapy for overactive bladder. The drug is applied daily to a region of the skin as a gel and has a good safety profile, the main side effect being dry mouth, which is predictable for an anti-cholinergic drug. As oxybutynin is one of the drugs that we found to prevent IENF depletion in diabetic rodents, we now propose a pilot clinical trial to determine whether Gelnique 3%TM, used off label in an investigator initiated study, can promote re-growth of IENF in a group of type 2 diabetic subjects with established peripheral neuropathy. We will take advantage of our prior experience using a clinical trial design that successfully showed efficacy of drug therapy in improving IENF density in type 2 diabetic subjects, to power the study appropriately and focus on neuropathy end points that are amenable to recovery. We will also enhance the earlier design by performing a double blind, placebo controlled study in subjects with type 2 diabetes and established peripheral neuropathy that will measure IENF density in skin biopsies collected before and 20 weeks after daily application of Gelnique 3%TM to the proximal leg as the primary end point. Secondary end points will be skin blood flow, quantitative sensory test values and quality of life score. We will also include an exploratory study of sudomotor function and sweat gland innervation that will provide data on autonomic neuropathy and assist development and validation of new biomarkers for this understudied aspect of diabetic neuropathy. Our intent in performing this pilot clinical trial is to illustrate that a therapeutic emerging from a focused preclinical drug discovery program can be rapidly translated to show demonstrable efficacy in diabetic subjects with peripheral neuropathy. The goal is to provide proof-of-concept data to support (or refute) the further development of muscarinic antagonists as a new and safe treatment for diabetic neuropathy.